[Show abstract][Hide abstract] ABSTRACT: Electrical high frequency stimulation (HFS) in the subthalamic nucleus (STN) has been shown to have a thera-peutic effect in several movement disorders. But, debilitating psychiatric effects like depression and suicidality are occa-sionally seen and might be caused by the changes in the serotoninergic activity. Previous studies could show that HFS of the STN results in inhibition of the serotonergic neurons originating in the dorsal raphe nucleus. The aim of this study was to characterize the effect of HFS (124 Hz, 0.5 mA) in the STN, on the extracellular levels of serotonin, dopamine and their metabolites HIAA, DOPAC and HVA in the caudate-putamen (CPu) in conscious and freely moving rats. Extracellular levels of the neurotransmitters and their metabolites were quantified using high performance liquid chromatography with electrochemical detection. Under HFS conditions, a significant reduction in the extracellular levels of serotonin was ob-served. Cessation of HFS showed a recovery back to basal levels. Dopamine levels were not affected, although significant increase of its metabolites DOPAC and HVA were measured. In the case of low frequency stimulation (LFS), levels of se-rotonin and its metabolite HIAA remained unchanged, while the levels of dopamine metabolites, DOPAC and HVA, showed a significant decline. These results demonstrate evidence for a strong linkage between HFS in the STN and reduc-tion of the levels of serotonin in the caudate-putamen, which is likely responsible for psychiatric side effects seen in Park-insonian patients who are treated with STN stimulation.
[Show abstract][Hide abstract] ABSTRACT: Retinoic acid (RA) is required for development and homeostasis of the normal mammalian brain and may play a role in the initiation and progression of malignant brain tumors, such as the glioblastoma multiforme (GBM) and the gliosarcoma (Gsarc). The subpopulation of stem-like glioma cells (SLGCs) was shown to resist standard glioma radio-/chemotherapy and to propagate tumor regrowth. We used phenotypically distinct, self-renewing SLGC lines from six human GBMs, two Gsarcs, and two subcloned SLGC derivatives in order to investigate their responsiveness to atRA and to identify the RA-receptor (RAR) isotypes involved. In general, atRA exerted a pro-proliferative and pro-survival effect on SLGCs, though the efficacy was distinct. By means of RAR isotype-selective retinoids we disclosed that these effects were mediated by RARα and RARγ, except for one SLGC line, in which the pro-proliferative signal was induced by the RARβ-selective retinoid. Only one GBM-derived cell line (T1338) and a subpopulation of another (T1389) displayed neural differentiation in response to atRA. Differentiation of T1338 was induced by RARα and RARγ isotype-selective retinoids, associated with down-regulation of Sox2, and the failure to induce orthotopic tumors in the brains of SCID mice. The differential responsiveness of the SLGC lines appeared unrelated to the expression of RARβ, as (i) atRA augmented RAR isotype mRNA expression and particularly rarβ mRNA in all SLGC lines, (ii) rarβ promoter hypomethylation in the SLGC lines was not related to differentiation and (iii) the induction of T1338 differentiation was by RARα- and RARγ-selective ligands.
[Show abstract][Hide abstract] ABSTRACT: The nucleus accumbens is selected as a surgical target in deep brain stimulation for treating refractory obsessive-compulsive disorder (OCD). One of the therapeutic benefits of this procedure is that the abnormal hyper-functioning prefrontal cortex of patients with OCD is restored during stimulation. One hypothesis regarding the mechanism of deep brain stimulation is that the neuronal electrophysiological properties are directly altered by electrical stimulation; another hypothesis assumes that the stimulation induces selective neuron transmitter release, such as γ-aminobutyric acid (GABA). In this study, we used multi-electrode arrays with electrode size of 40 × 40 μm to record electrophysiological signals from the large nucleus accumbens neurons in acute rat brain slices while applying electrical stimulation simultaneously. We revealed that high-frequency stimulation (HFS, 140 Hz) suppressed the spontaneous neuronal firing rate significantly, whereas low-frequency stimulation (LFS, 10 Hz) did not. Both HFS and LFS have no effect on neuronal firing pattern or on neuronal oscillation synchrony. GABAB receptor antagonism reversed the HFS-provoked neuronal inhibition, whereas GABAA receptor blockade failed to affect it. The recorded neurons were pharmacologically identified to be cholinergic interneurons. We propose that HFS has a direct suppressive effect on the identified accumbal acetylcholine (ACh) interneurons by enhancing GABA release in the stimulated region. Potentially, suppressed ACh interneurons decrease the disinhibiting function of medium-sized spiny neurons in the striato-thalamo-cortical circuit. This finding might give an indication of the mechanism of the therapeutic effect of HFS in nucleus accumbens on restoring the abnormal hyperactive prefrontal cortex status in OCD.
European Journal of Neuroscience 08/2014; in press. · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Essential tremor is the most common type of tremor, with a prevalence of 0.4% in the overall population and 4-7% in persons over age 65. In general, tremor is so common that patients with tremor are frequently treated not only by neurologists, but also by physicians from other specialties.
This review is based on publications retrieved by a selective PubMed search and on guidelines from Germany and abroad.
Particular tremor syndromes are usually diagnosed on the basis of their typical clinical presentation and whatever accompanying manifestations may be present. Ancillary tests are usually unnecessary. Unilateral rest tremor accompanied by rigidity and bradykinesia is typical of Parkinson's disease. Essential tremor is a bilateral postural tremor. The most common cause of intention tremor is multiple sclerosis. Mild tremor syndromes can often be treated satisfactorily with drugs. In case of severe tremor, which is rarer, a stereotactic operation can be considered. The usual outcome of such procedures is the complete suppression of tremor.
Most patients with tremor can be given a precise diagnosis and offered specific treatment. It is important for the physician to inform the patient about the expected course of tremor over time, its possible genetic causes, and the various available treatments.
Deutsches Ärzteblatt International 03/2014; 111(13):225-36. · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This retrospective study investigated the outcome of patients with brain metastases after radiosurgery with special emphasis on prognostic impact of visible intratumoral necrosis on survival and local control.
From 1998 through 2008, 149 patients with brain metastases from solid tumors were treated with stereotactic radiotherapy at Luebeck University. Median age was 58.4 years with 11%, 78%, 10% in recursive partitioning analysis (RPA) classes I, II, III, respectively. 70% had 1 metastasis, 29% 2-3 metastases, 2 patients more than 3 metastases, 71% active extracranial disease. Median volume of metastatic lesions was 4.7 cm3, median radiosurgery dose 22 Gy (single fraction). 71% of patients received additional whole-brain irradiation (WBI). All patients were analyzed regarding survival, local, distant failure and prognostic factors, side effects and changes in neurologic symptoms after radiotherapy. The type of contrast-enhancement in MR imaging was also analyzed; metastatic lesions were classified as containing necrosis if they appeared as ring-enhancing with central areas of no or minimal contrast enhancement.
Median survival was 7.0 months with 1-year and 5-year survival rates of 33% and 0.4%, respectively. Tumor necrosis (ring-enhancement) was visible on pretreatment MRI scans in 56% of all lesions and lesions with necrosis were larger than non-necrotic lesions (6.7 cm3 vs. 3.2 cm3, p = 0.01). Patients with tumor necrosis had a median survival of 5.4 months, patients without tumor necrosis 7.2 months. Local control rate in the irradiated volume was 70%, median survival without local failure 17.8 months. Control in the brain outside the irradiated volume was 60%, median survival without distant failure 14.0 months. Significant prognostic factors for overall survival were KPS (p = 0.001), presence of tumor necrosis on pretreatment MRI (p = 0.001) with RPA-class and WBI reaching marginal significance (each p = 0.05). Prognostic impact of tumor necrosis remained significant if only smaller tumors with a volume below 3.5 cm3 (p = 0.03). Side effects were rare, only one patient suffered from serious acute side effects.
Results of this retrospective study support that stereotactic radiotherapy is an effective treatment option for patients with metastatic brain lesions. The prognostic impact of visible tumor necrosis (ring-enhancement) on pretreatment MRI scans should be further investigated.
[Show abstract][Hide abstract] ABSTRACT: Kompetenzorientierung in der medizinischen Ausbildung gilt als Voraussetzung, um Studierende auf die Erfordernisse des Arztberufes vorzubereiten. Die Formulierung eines verbindlichen Fachqualifikationsrahmens ist ein Meilenstein in diese Richtung. Mit dem Nationalen Kompetenzbasierten Lernzielkatalog Medizin (NKLM) schaffen der Medizinische Fakultätentag (MFT) und die Gesellschaft für Medizinische Ausbildung (GMA) die Basis für ein Kernkurrikulum bis zur Approbation zur Ärztin bzw. zum Arzt. Die Chirurgische Arbeitsgemeinschaft Lehre der Deutschen Gesellschaft für Chirurgie (DGCH – CAL) möchte mit dem Nationalen Lernzielkatalog Chirurgie eine Brücke zwischen NKLM und Lernzielkatalogen an den medizinischen Fakultäten schlagen. Er soll die Basis für ein chirurgisches Kernkurrikulum darstellen und die Sichtbarkeit unseres Faches in der studentischen Ausbildung stärken. Auf der Grundlage verschiedener Lernzielkataloge an medizinischen Fakultäten, des Lernzielkatalogs für Orthopädie-Unfallchirurgie und des Schweizer Lernzielkatalogs erfolgte mit Vertretern aller chirurgischen Fachgesellschaften ein strukturierter Selektionsprozess für Lernziel-Items sowie die Definierung von Kompetenzebenen und Kompetenzbereichen. Nach Komplettierung wird der Lernzielkatalog in elektronischer Form auf der Webseite der DGCH zugänglich gemacht werden.
[Show abstract][Hide abstract] ABSTRACT: Competency-based medical education is a prerequisite to prepare students for the medical profession. A mandatory professional qualification framework is a milestone towards this aim. The National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) of the German Medical Faculty Association (MFT) and the German Medical Association will constitute a basis for a core curriculum of undergraduate medical training. The Surgical Working Group on Medical Education (CAL) of the German Association of Surgeons (DGCH) aims at formulating a competency-based catalogue of learning objectives for surgical undergraduate training to bridge the gap between the NKLM and the learning objectives of individual medical faculties. This is intended to enhance the prominence and visibility of the surgical discipline in the context of medical education. On the basis of different faculty catalogues of learning objectives, the catalogue of learning objectives of the German Association of Orthopedics and Orthopedic Surgery and the Swiss Catalogue of Learning Objectives representatives of all German Surgical Associations cooperated towards a structured selection process of learning objectives and the definition of levels and areas of competencies. After completion the catalogue of learning objectives will be available online on the webpage of the DGCH.
[Show abstract][Hide abstract] ABSTRACT: A well-established navigation method is one of the key conditions for successful brain surgery: it should be accurate, safe and online operable. Recent research shows that optical coherence tomography (OCT) is a potential solution for this application by providing a high resolution and small probe dimension. In this study a fiber-based spectral-domain OCT system utilizing a super-luminescent-diode with the center wavelength of 840 nm providing 14.5 μm axial resolution was used. A composite 125 μm diameter detecting probe with a gradient index (GRIN) fiber fused to a single mode fiber was employed. Signals were reconstructed into grayscale images by horizontally aligning A-scans from the same trajectory with different depths. The reconstructed images can display brain morphology along the entire trajectory. For scans of typical white matter, the signals showed a higher reflection of light intensity with lower penetration depth as well as a steeper attenuation rate compared to the scans typical for gray matter. Micro-structures such as axon bundles (70 μm) in the caudate nucleus are visible in the reconstructed images. This study explores the potential of OCT to be a navigation modality in brain surgery.
Physics in Medicine and Biology 01/2013; 58(3):555-568. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A long term functional and reliable coupling between neural tissue and implanted microelectrodes is the key issue in acquiring neural electrophysiological signals or therapeutically excite neural tissue. The currently often used rigid micro-electrodes are thought to cause a severe foreign body reaction resulting in a thick glial scar and consequently a poor tissue-electrode coupling in the chronic phase. We hypothesize, that this adverse effect might be remedied by probes compliant to the soft brain tissue, i.e., replacing rigid electrodes by flexible ones. Unfortunately, this flexibility comes at the price of a low stiffness, which makes targeted low trauma implantation very challenging. In this study, we demonstrate an adaptable and simple method to implant extremely flexible microprobes even to deep areas of rat's brain. Implantation of flexible probes is achieved by rod supported stereotactic insertion fostered by a hydrogel (2% agarose in PBS) cushion on the exposed skull. We were thus able to implant very flexible micro-probes in 70 rats as deep as the rodent's subthalamic nucleus. This work describes in detail the procedures and steps needed for minimal invasive, but reliable implantation of flexible probes.
[Show abstract][Hide abstract] ABSTRACT: Background: Cerebrospinal fluid (CSF) leaks are well-known and frequent complications of intracranial pro-cedures. Numerous studies have focused on the clinical aspects of incidence, risk factors, outcome, treatment, and prevention; however, large prospective multicenter studies are missing. The aim of this study was to prospec-tively analyze the rate of CSF leaks and their causes. Method: A total of 545 patients with a variety of intra-cranial procedures (elective and trauma) were recruited in a multicenter, prospective, observational study over a 12-month period. Results: In 545 cranial surgeries, we observed a CSF leak rate of 7.7% (n = 42) at the time of discharge from the hos-pital. Significant risk factors for CSF leaks were poste-rior fossa surgery, opened pneumatized spaces, patients younger than 66 years, size of craniotomies, craniecto-mies rather than craniotomies, remaining dura defects larger than 1 cm, and wound closure without using muscle sutures, continuous locked, or unlocked sutures. Non-significant risk factors for CSF leaks were revision crani-otomies, craniotomies for different pathologies, previous radiotherapy and/or systemic chemotherapy, augmenta-tion of dura sutures with various materials, and wound drains as well as temporary CSF drains. Conclusion: Despite the number of techniques and devel-opments for dural closure, the problem of CSF leaks remains evident and further improvement has to be made.
[Show abstract][Hide abstract] ABSTRACT: Background Severe forms of primary dystonia are diffi cult to manage medically. We assessed the safety and effi cacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial.
The Lancet Neurology 10/2012; 11(12):1029-1038. · 21.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current quest for brain-machine-interfaces is hindered by the need to find a reliable solution for truly chronic brain implants. One approach to tackle that problem is not only to use flexible, mechanically compliant micro recording probes, but to enhance their acceptance in the target tissue by biologization. In order to shed light on the best modifica-tions, immunohistochemical staining of long term implants in rat brains provided thousands of images over a six month experimental phase. The current work explains the image processing method, how these images were analysed in the least ambiguous way to provide meaningful and statistically relevant results. Quantitative analysis of the images al-lowed for the comparison of changes within the image and comparison between different images.
[Show abstract][Hide abstract] ABSTRACT: As was proposed earlier, mobile devices may be integrated into the clinical workflow or daily activity by supporting documentary procedures or self-paced medical log keeping (Hofmann et al. 2009). However, due to security reasons up till now only dedicated workstations at the primary care provider's desk were intended to retrieve collected data from the mobile logging device. We propose an extension of this scheme to securely upload and process collected data by ad hoc web-service connections. In our case, we use a touch interfaced handheld device to assess pain levels by an elec-tronic Visual Analog Scale. The individually identifiable handheld collects and stores its patient's input, until a WLAN connection is sensed. It then transfers the data on a Cloud-located SQL based sever for further storage and competent retrieval. The communication between handheld and server is based on an authentificated, secure SHTTP protocol. This way, an authenticated, but remote computer based tool can access the data from the SQL Database for further clinical assessment. Mobile devices are used in a clinical setting to log volunteer's "pain" levels in parallel to usual physical log keeping. Data are transferred asynchronously and without user interaction to the analysis desktop by utilizing the Insti-tutes WLAN infrastructure. Given our preliminary results, it appears reasonable to utilize the usability and acceptance of modern handheld devices to asynchronously log and transfer even sensitive medical data over secure internet connec-tions.
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in PD. However, QoL fails to improve in a relevant proportion of patients. We studied clinical baseline and progression parameters associated with improvement in QoL after DBS. Data from a German randomized, controlled study comparing DBS (60 patients) with best medical treatment (59 patients) were analyzed. Changes in patients' QoL were assessed using the Parkinson's Disease Questionnaire (PDQ-39) at baseline and at the 6-month follow-up. For the STN-DBS patients, the changes in PDQ-39 were correlated with predefined clinical preoperative and progression parameters. Scores for QoL improved after STN-DBS for 57% of the patients, and for 43% patients, they did not improve. Patients with improvement in QoL showed significantly higher cumulative daily "off" time. Changes in the PDQ-39 showed a significant positive correlation with the cumulative daily off time at baseline. Logistic regression analysis revealed that 1 additional hour off time at baseline increases the odds for improvement on PDQ-39 by a factor of 1.33 (odds ratio). In the postoperative course, changes in the PDQ-39 significantly correlated with the reduction of cumulative daily off time, an improvement on the UPDRS (UPDRS III off), and positive mood changes. Among the baseline parameters, the cumulative daily off time is the strongest predictor for improvement in disease-related QoL after DBS. Improvement in QoL after STN-DBS is also correlated with changes in motor functions and changes in depression and anxiety.
Movement Disorders 12/2011; 26(14):2516-21. · 5.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebrospinal fluid (CSF) leaks are well-known and frequent complications of intracranial procedures with their clinical aspects covered by numerous studies. Little, however, is known about the pharmacoeconomical aspects of this specific complication. 545 patients with a variety of intracranial procedures (elective and trauma) were recruited for a multicenter, prospective, observational study over a 13-month period. A specific pharmacoeconomic analysis was performed in 168 of these patients from the institution of the first author covering all clinical and pharmaco-economical aspects of this specific complication. Of all patients, 5.36% developed a postoperative CSF leak. Treatment of the leak required numerous diagnostic and therapeutic procedures such as reoperations (n=6), lumbar punctures (n=11) or lumbar drainages (n=4). Costs for these procedures and prolonged hospital stays nearly doubled the costs per case (€ 14 079/case without a fistula vs. € 25 499/case with a fistula). Reimbursement for the hospital covered these extra costs, but net earnings per case were diminished by € 565 in cases with a CSF leak. The authors conclude that the presence of a CSF leak after an intracranial operation - although not influencing outcome in general - results in additional diagnostic and therapeutic procedures for the patient, an enormous increase in costs for the community, and a financial loss for the hospital. Strategies to lower this complication rate should therefore urgently be developed both from a clinical and a pharmacoeconomical point of view.
Journal of neurological surgery. Part A, Central European neurosurgery. 09/2011;